Twenty five years ago, Christopher Lipinski and colleagues published arguably the most influential sentence in small-molecule drug discovery. Their cleverly crafted ‘rule of 5’ (Ro5) mnemonic was adopted into everyday medicinal chemistry practice and has influenced a generation of small-molecule drug discovery scientists. Five times five years later, we consider the impact of the Ro5 and ask to what extent it should still guide today’s medicinal chemistry efforts.
This is a preview of subscription content, access via your institution
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 per month
cancel any time
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3–25 (1997).
Shultz, M. D. Two Decades under the influence of the rule of five and the changing properties of approved oral drugs. J. Med. Chem. 62, 1701–1714 (2019).
Dowden, H. & Munro, J. Trends in clinical success rates and therapeutic focus. Nat. Rev. Drug Discov. 18, 495–496 (2019).
Jhoti, H., Williams, G., Rees, D. C. & Murray, C. W. The ‘rule of three’ for fragment-based drug discovery: where are we now? Nat. Rev. Drug Discov. 12, 644 (2013).
Young, R. J. & Leeson, P. D. Mapping the efficiency and physicochemical trajectories of successful optimizations. J. Med. Chem. 61, 6421–6467 (2018).
Doak, B. C. & Kihlberg, J. Cyclophilin succumbs to a macrocyclic chameleon. J. Med. Chem. 61, 9469–9472 (2018).
Kofink, C. et al. A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo. Nat. Commun. 13, 5969 (2022).
DeGoey, D. A., Chen, H.-J., Cox, P. B. & Wendt, M. D. Beyond the rule of 5: lessons learned from AbbVie’s drugs and compound collection. J. Med. Chem. 61, 2636–2651 (2018).
Tucker, T. J. et al. A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors. J. Med. Chem. 64, 16770–16800 (2021).
I.V.H. is an employee of Merck Healthcare KGaA. B.R.H. and A.C. are employees of EMD Serono, Inc.
Rights and permissions
About this article
Cite this article
Hartung, I.V., Huck, B.R. & Crespo, A. Rules were made to be broken. Nat Rev Chem 7, 3–4 (2023). https://doi.org/10.1038/s41570-022-00451-0
This article is cited by
Sorry, this item is not (bio)available
Nature Reviews Chemistry (2023)